The aim of this Program's revised renewal application is to clarify the mechanisms of methamphetamine (METH) potentiation of HIV neural injury. Given the prevalence of co-infection with hepatitis C (HCV), as well as the growing awareness of HCV as a co-factor in neural injury, the Program will examine the separate and combined effects of HIV, METH and HCV. Scientific hypotheses for the Program are based on an overall model proposing that HIV, METH and HCV can act both directly and indirectly through immune cell activation that alters the balance between neuroprotective and neurotoxic mediators, leading to injury of specific neuronal subpopulations in the neocortex and nigrostriatum. The Program utilizes a multifaceted and translational approach through six Projects (Neurocognitive, Neuromotor, fMRI, Carbon 13 Spectroscopy, Biomarkers, Neurobiology). Innovative directions include deployment of neurocognitive, neuromotor, and neuroimaging methods hypothesized to be more sensitive and specific in detecting underlying mechanisms of injury from HIV, METH, and HCV and linking these to in vivo and in vitro molecular studies. Programmatic scientific leadership, synergy, coordination, basic evaluating, and effective use of shared resources are provided by a Core served by the Executive, Participant Accrual and Retention, Data Management and Information Systems, Statistics, and Clinical Assessment Units. Through coordinated multidisciplinary research addressing the neurotoxic effects of HIV, METH and HCV at different levels of analysis we hope to achieve a more precise understanding of the nature and mechanisms of neural injury attributable to these factors. Understanding these mechanisms will provide a basis for the future development of targeted treatment interventions. The application has been strengthened by attending to reviewer concerns regarding participant recruitment and approach to confounds;by providing new preliminary data in the revised projects to support their feasibility and refine their hypotheses;and clarifying each Project's role in the Program's overall aims, as well as their synergy and interaction among themselves.